Mycobacterium is a genus of bacteria which are aerobic, mostly slow growing, slightly curved or straight rods, sometimes branching and filamentous, and distinguished by acid-fast staining. They are sometimes referred to as acid-fast bacilli (AFB) as application of alcohol (e.g., acid-alcohol or 95% ethanol with 3% hydrochloric acid) will not decolorize bacilli stained with basic dye. Typically, the mycobacteria are obligate aerobes, and they can be characterized as gram-positive. However, some have stated that gram-staining is unhelpful or unclassifiable. The genus mycobacterium includes the highly pathogenic organisms that cause tuberculosis (M. tuberculosis and sometimes M. bovis) and leprosy (M. leprae). There are many other species of mycobacterium, some of which are important in veterinary medicine.
The following species of the genus mycobacterium are known pathogens for humans, and some are pathogenic for certain animals as well: M. tuberculosis, M. leprae, M. avium-intracellulare, M. bovis, M. chelonei (also known as borstelense and abscessus), M. africanum, M. marinium (also known as balnei and platypoecilus, the causative agent of "swimming pool granuloma"), M. buruli (also known as ulcerans), M. fortuitum (also known as giae, minetti, and ranae), M. haemophilum, M. intracellulare, M. kansasii (also known as luciflavum), M. littorale (also known as xenopi), M. malmoense, M. marianum (also known as scrofulaceum and paraffinicum), M. simiae, M. szulgai, and M. ulcerans (which is the agent responsible for Buruli ulcer).
Mycobacterium which are pathogenic for animals but not believed to be pathogenic for humans include the following: M. avium (also known as brunense), M. flavascens, M. lepraemurium, M. microti, and M. paratuberculosis (which is the causative agent for Johne's Disease). The following species of the genus mycobacterium are believed to be non-pathogenic: M. gordonae (also known as aquae), M. gastri, M. phlei (also known as moelleri and as timothy bacillus), M. nonchromogenicum, M. smegmatis, M. terrae, M. triviale, and M. vaccae.
Additionally, certain mycobacteria other than M. tuberculosis and M. bovis are alternatively known as non-tuberculosis mycobacteria. They are divided into four groups, also known as Runyon groups, based on pigmentation and growth rate. Each group includes several species. Group I refers to slow-growing photochromogens; Group II refers to slow-growing scotochromogens; Group III refers to slow-growing nonphotochromogens; and Group IV refers to rapidly-growing mycobacteria. The non-tuberculosis mycobacteria are also called atypical or anonymous mycobacteria.
Tuberculosis (TB) is an acute or chronic infection caused by M. tuberculosis and occasionally by M. bovis. Tuberculosis continues to be a major health concern in both the United States and abroad, exacting a yearly mortality of 3 million lives. See Styblo, et al., Bull. Int. Union Tuberc. 56:118-125 (1981). Of special concern is the increased risk to HIV-positive persons who are either exposed to the tubercle bacilli for the first time or are subject to reinfection/reactivation of dormant lesions. See, Styblo, Rev. Inf. Dis. 11:Suppl. 2, S339-S346 (1989). In addition, the appearance of multiply drug-resistant strains of Mycobacterium tuberculosis is urban areas in developed countries places many new populations at risk. See, Snider, et al., N. Eng. J. Med. 326:703-705 (1992). According to the World Health Organization's estimates, 1.7 billion people (one-third of the world population) are infected with the tubercle bacilli. Sixty million people are currently afflicted with active Mycobacterium tuberculosis, another 10 million cases arise annually and more than 3 millions die each year. See, Kaufman, et al., Trends in Microbiology 1:2-5 (1993). This means that tuberculosis is responsible for 6% of the total global mortality and more than 25% of all preventable deaths. In 1992, about 26,000 cases of active TB were reported in the United States, an 18% increase since 1988. Similar increases have been observed in many European countries; 33% in Switzerland, 30% in Denmark, 20% in Norway, 18% in Ireland, 17% in Austria, 9% in The Netherlands, 5% in Sweden and 4% in the United Kingdom. See, Kaufman, ibid. There are also a significant number of AIDS patients who become infected with TB. It has been estimated that worldwide there are 4.4 million people co-infected with HIV and tuberculosis and in some African states, 40% of tuberculosis patients are HIV-positive.
Although commonly thought of as a pulmonary infection, TB is well known to afflict many parts of the body. In addition to pulmonary TB, examples of other foci of tubercular infection include miliary TB (generalized hematogenous or lymphohematogenous TB), central nervous system TB, pleural TB, TB pericarditis, genitourinary TB, TB of the gastrointestinal tract, TB peritonitis, TB of the adrenals, TB of the liver, TB of the bones and joints (for example, TB spondylitis or Pott's Disease), TB lymphadenitis, and TB of the mouth, middle ear, larynx, and bronchial tree.
Tuberculosis has been characterized as a life-long balance between the host and the infecting organism. Pulmonary or extrapulmonary foci may reactivate at any time, often after long periods of latency. Prevention of TB has been attempted by vaccination with BCG, which is an attenuated strain of M. tuberculosis.
Chemoprophylaxis of TB is practiced in appropriate cases and generally consists of isoniazid. Usually, chemoprophylaxis is recommended in selected individuals who are tuberculin-positive (by a skin test, discussed below) without overt disease. Examples include very young adults and children, recent tuberculin converters, individuals with pulmonary infiltrates of unknown ideology, people receiving prolonged corticosteroid therapy, postgastrectomy patients with roentgen evidence of inactive pulmonary TB, and all patients with silicosis. Occasionally, treatment of tuberculin-negative individuals is appropriate. Examples include an infant suffering a brief exposure to a known infection and persons having reduced immune responsiveness.
Some of the signs and symptoms of pulmonary TB are cough, sputum production, hemoptysis, pain in the chest wall or pleural pain, dyspnea, and, in the case of extrapulmonary TB, signs and symptoms related to the infected foci. Frequently, a patient remains asymptomatic for prolonged periods of time.
Definitive diagnosis by cultural identification of the causative agent is preferred. The tuberculin test is an adjunct to diagnosis. A standard tuberculin test is performed with purified protein derivative (PPD) administered intradermally (the Mantoux test). Various modifications include Pirequet's (scratch) test, multiple-puncture tine and Heaf tests. Because the diagnosis of TB can be elusive, particularly in its extrapulmonary forms, tissue biopsy may be indicated to obtain a sample for acid-fast staining and culture studies.
Conventional therapy for TB includes treatment with isoniazid, ethambutol, streptomycin, rifampin, rifabutin, clarithromycin, ciprofloxacin, clofazamine, azithromycin, ethionamide, amikacin and resorcinomycin A. In rare cases, isoniazid may be used alone. However, the usual initial treatment for pulmonary tuberculosis includes isoniazid in combination with at least one other drug, such as ethambutol, streptomycin, rifampin or ethionamide. Retreatment of pulmonary tuberculosis typically involves drug combinations including rifampin and other drugs as noted above. Development of resistance of the causative agent to anti-TB drugs, especially isoniazid, is well known. Extrapulmonary tuberculosis is also usually treated with a combination including rifampin and at least one of the other three drugs mentioned.
The anti-TB antibiotic isoniazid (isonicotinic acid hydrazide) is frequently effective, but isoniazid often causes severe, sometimes fatal, hepatitis. The risk of hepatitis increases with the patient's age. Additionally, isoniazid causes peripheral neuropathy in some recipients in a dose-related fashion. Rifampin, another antibiotic used to treat TB, must be used in conjunction with another drug such as isoniazid. This requirement for combination therapy with rifampin applies to the initial treatment as well as the retreatment of pulmonary TB.
Usually, isoniazid, rifampin, ethambutol and ethionamide are given orally. Streptomycin is typically given intramuscularly. Amikacin is given intramuscularly or intravenously. Clofazimine, which is also used to treat leprosy, is given orally.
Amikacin is a semisynthetic aminoglycoside antibiotic derived from Kanamycin A. For its preparation see U.S. Pat. No. 3,781,268. For a review see Kerridge, Pharmacological and Biochemical Properties of Drug Substances 1:125-153, M. E. Goldberg, ed. (1977). Amikacin is usually administered intramuscularly or intravenously. For additional information including clinical pharmacology, indications, side effects and dosages, see the Physicians Desk Reference, 42 ed. (1988) at pages 744-746 (hereinafter, PDR).
Clofazimine is an antibacterial agent also known as LAMPRENE.RTM.. For its preparation, see Barry, et at., Nature 179:1013 (1957). For a review see Karat, et at., Brit. Med. J. 3:175 (1971). Clofazimine is generally given orally. For additional information including clinical pharmacology, precautions and dosages, see the PDR at page 982.
Ethionamide is an antibacterial agent also known as AMIDAZINE.RTM. and TRECATOR.RTM.. See British Patent No. 800,250. This drug is typically given orally. For further information including precautions and dosages, see the PDR at page 2310.
Ciprofloxacin is a broad spectrum synthetic antibacterial agent for oral usage. It is also known as CIPRO.RTM.. It is typically given in total daily dosages of 500 to 1,000 milligrams which is usually given in 2 equal doses in 24 hours. For further information see the PDR (1989) at pages 1441-1443.
Leprosy or Hansen's Disease is a chronic infectious disease caused by M. leprae. Leprosy is conveniently divided into four types, namely indeterminate leprosy, tuberculoid leprosy, lepromatous leprosy, and dimorphous (borderline) leprosy. In any of its forms, leprosy is characterized by invasion of the peripheral nerves by the causative agent. Usually, a lack of sensation or anesthesia is produced in the relevant skin area. Paralysis and deformity follow sensory loss. Diagnosis is typically established by biopsy. Conventional treatment includes administration of dapsone (4,4'-diaminodiphenyl sulfone, DDS). Dapsone is typically given orally for prolonged periods, such as for two years after diagnosis. For certain forms of leprosy, such as the dimorphous and lepromatous forms, combination therapy with rifampin and/or dapsone is administered. Sometimes the drug clofazimine is given alone or in combination with dapsone. Dapsone alone is the conventional therapy for indeterminate and tuberculoid types of leprosy.
Because of some of the difficulties and inadequacies of conventional therapy for TB and other mycobacterial infections, new therapeutic modalities are desirable.